The goal of this project is to learn more about the control of movement in normal humans and in patients with voluntary movement disorders such as Parkinson's disease, dystonia, and cerebellar ataxia. The tools we use include clinical neurophysiological methods such as electroencephalography (EEG), magnetoencephalography (MEG), electromyography (EMG), and transcranial magnetic stimulation (TMS) and neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). [unreadable] A number of efforts in the laboratory are devoted to understanding the physiology of volition and its pathophysiology in a number of disorders. To determine which areas of the brain are activated with the sense of agency (personal control) when making voluntary movement, we have developed an MRI-compatible dataglove which subjects will wear while making hand movements in the scanner. Subjects will be able to view their movements in real-time and the visual feedback they receive will be varied during the experiment to simulate different degrees of voluntary control. Correlative EEG studies will also be done. Two studies looking at the subjective sense of volition in movement disorders are nearing completion. One study in patients with schizophrenia showed that they experienced the ?will? to move much closer to movement onset than healthy volunteers. In a similar study, in patients with Tourette Syndrome, we are finding that their experience of ?will? is similar to healthy volunteers for voluntary movements.[unreadable] We are trying to determine EEG and MEG methods to predict in real time when someone is going to move and what movement they will make. We have optimized features and classification methods for the prediction. The results demonstrate that we can robustly predict in real-time when a person wants to movement and whether this will be with the right or left hand. Using MEG, our data shows that we can also determine whether someone will move their right hand into the left or right spatial field. We are now trying to extend these results to patients with stroke and primary lateral sclerosis. The work should be relevant for use with a brain-computer interface, as well as being useful to understand the physiology of volition.[unreadable] The brain structures responsible for coordinating temporal aspects of bimanual movement have not yet been identified. Previous studies suggest that the corpus callosum and interhemispheric information transfer may be important for spatial coordination and less so for temporal coordination. This difference may be demonstrated through studying EEG coherence patterns, which seem to support this hypothesis.[unreadable] A major effort in the laboratory is devoted to understanding dystonia. In focal hand dystonia, we have just completed two studies examining the role of sensory afferent stimulation on motor output. They have shown that these two sensory circuits do not contribute to the impaired surround inhibition in dystonia. We are now engaged in understanding the premotor to motor cortex interactions in focal hand dystonia. We are also exploring the physiology of motor learning in dystonia. In one set of experiments, we are evaluating the efficacy of two different plasticity protocols on measures of cortical excitability and inhibition. For one of the methods we found significant effects similar to long-term potentiation (LTP) on intracortical and afferent induced inhibition in patients and control subjects. We are also conducting a case-control experimental study to evaluate long-term learning of sequential finger movements in focal hand dystonia patients. We have studied the mechanisms underlying the somesthetic discrimination deficit in focal hand dystonia using EEG. We showed that the recovery function of cortical somatosensory evoked potential (SEP) component in the paired-pulse paradigm was shown to be impaired and that this was well correlated with somesthetic temporal discrimination capability.[unreadable] In the area of dystonia treatment, we continue to provide botulinum toxin injections to our patients while training physicians to perform these injections. We are also conducting a therapeutic trial of transcranial direct current stimulation (tDCS) of the brain in patients with focal hand dystonia. For patients with blepharospasm, we are evaluating the efficacy of various types of non-invasive brain stimulation. Low frequency repetitive TMS, theta burst stimulation and tDCS are being compared.[unreadable] The genetic markers in focal dystonia are largely unknown. Currently, we are evaluating patients with all forms of focal dystonia (blepharospasm, Meige syndrome, cervical dystonia, focal hand dystonia and spasmodic dysphonia) to look for a genetic marker. The study involves large families with focal dystonia and individuals without a family history. We are also conducting a blink reflex study in patients with craniofacial dystonia and their first degree relatives. The goal of this study is to determine if there is an underlying neurophysiological marker present in unaffected relatives.[unreadable] Although fatigue is one of the most common symptom in Parkinson disease (PD), its characteristics and etiology are largely unknown because it is a subjective, complicated symptom hard to evaluate. With objective measurement, we are planning to study the clinical features and the beneficial effect of levodopa and repetitive transcranial magnetic stimulation. The pathophysiology of medication-related compulsive behaviors (pathological gambling and hypersexuality) in PD is poorly understood. We have completed a study on the prevalence of obsessive compulsive and impulse control symptoms in PD compared to focal hand dystonia, and results are being analyzed. We are doing a trial of tDCS to see if this will improve gait in patients with PD. In other studies, we are evaluating a new device to see if it can provide objective evidence of motor deterioration in early PD, and we are collaborating with investigators in NIA on the clinical aspects of patients with genetic forms of PD.